Significant effort has been invested in the design of colloidal drug carriers in order to improve drug localization and bioavailability. Ideally, an actively targeted particulate drug carrier will increase the therapeutic efficacy of a drug by delivery to the diseased site, while reducing drug-associated side effects. Attainment of this goal would greatly advance treatment of diseases (e.g., cancer) where the toxic effects of therapeutics administered systemically may outweigh their benefit. To date, many types of delivery vehicles have been explored for in vitro and in vivo drug delivery applications, including inorganic nanoparticles, polyelectrolyte complexes, liposomes, block co-polymer micelles, and polymeric nanoparticles.
A particularly compelling phenomenon from the standpoint of cancer therapy is RNA interference (RNAi). RNAi is a relatively new approach to gene silencing, which has been demonstrated effective both in vitro and in vivo. This technique generally employs small 21-25 nucleotide long double stranded small interfering RNAs (or siRNAs) to inhibit gene expression through degradation of a targeted mRNA. Whereas the potential for therapeutic oncology applications exist where siRNA would be used to specifically shut down genes necessary for tumor growth, the lack of efficient methods for in vivo siRNA delivery prevent widespread therapeutic use. In addition to the confounding issues associated with systemic, intravenous delivery of siRNA, its polyanionic nature and high molecular weight (˜13 kDa) prevent transport across the cell membrane. Thus, effective siRNA carriers must enable efficient transport through the vasculature to the tumor, and then must additionally enable intracellular delivery of the cargo.
A common method currently used for siRNA delivery in vitro employs cationic lipid-based carriers or polyelectrolytes. These charged moieties form polyplexes with the siRNA, forming aggregates that can be taken up into the cells, thereby delivering the siRNA to the cytosol. However, these carriers can have notable drawbacks with respect to toxicity and difficulties in specific cell targeting, thereby giving rise to a need for alternative delivery methods. A number of new approaches have been reported that overcome some of the shortcomings of lipid-based approaches. For example, Schiffelers et al. used an RGD (Arg—Gly—Asp peptide ligand)-PEG-PEI complex to target siRNA to tumor neovasculature. (Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32 (2004)). Song et al. presented the use of a protamine-antibody fusion protein using the Fab fragment of HIV-1 envelope antibody for siRNA delivery. (Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat. Biotechnol. 23, 709-717 (2005)). Another targeting motif has been the use of liposomes in the form of an immunoliposome complex reported by Pirollo et al. (Materializing the Potential of Small Interfering RNA via a Tumor-Targeting Nanodelivery System. Cancer Res. 67, 2938-2943 (2007)). A number of other similar approaches have been taken and these siRNA carriers have enabled certain degrees of success. However, issues of toxicity, leakiness, and payload capacity still persist, especially in the context of in vivo gene silencing.
Accordingly, there is a need for systems and methods for the efficient cellular delivery of therapeutics. It is to the provision of such systems and methods for the efficient cellular delivery of therapeutics using nanogel-based technologies that the various embodiments of the present invention are directed.